CN110330543A - 3- acetyl group -5- hydroxyl-B- norcholesterol -6-(N- methyl) contracting ammonia sulphur hydrazone, preparation method and its usage - Google Patents
3- acetyl group -5- hydroxyl-B- norcholesterol -6-(N- methyl) contracting ammonia sulphur hydrazone, preparation method and its usage Download PDFInfo
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- CN110330543A CN110330543A CN201910704702.0A CN201910704702A CN110330543A CN 110330543 A CN110330543 A CN 110330543A CN 201910704702 A CN201910704702 A CN 201910704702A CN 110330543 A CN110330543 A CN 110330543A
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- methyl
- acetyl group
- norcholesterol
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- ammonia sulphur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Abstract
The invention discloses a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone, preparation method and its usage, the structural formula of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) the contracting ammonia sulphur hydrazone is as follows:
Description
[technical field]
The invention belongs to field of medicine preparing technology, and in particular to a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6-
(N- methyl) contracting ammonia sulphur hydrazone, preparation method and its usage.
[background technique]
Cancer is to endanger a kind of principal disease of human health, captures the problem that malignant tumour is modern medicine,
It is the maximum challenge of medical industry processed now.Currently, various types of anti-tumor drug continuously emerges and clinically obtains
The anti-tumor drug that must be applied, but clinically use is more toxic caused by tissue as it, is greatly limited
Their use scope.Therefore, finding efficient, highly selective and Small side effects anticancer drug is the main of anticancer drug exploitation
Direction.
Document report hydrazone compounds and its derivative compound have physiological activity antitumor well, to Hey-
1B (Proliferation of Human Ovarian Cell), SKBR3 (human breast carcinoma) etc. have the function of external Inhibit proliferaton growth (Khan S well
A,Asiri AM,Yusuf M.Synthesis and biological evaluation of some thiazolidinone
derivatives of steroid as antibacterial agents[J].European Journal of
Medicinal Chemistry,2009,40(36):2597-2600).With going deep into steroidal hydrazone compounds research, mesh
It is preceding to have synthesized various structures uniqueness, the excellent steroidal hydrazone compounds of physiological activity.Cholesteric B- drop also has antitumor well
Activity, related personnel have been chemically modified the correlative study of transformation to cholesterol, as " one kind has Chinese invention patent
B- drop-D-homo- lactams the steroidal compounds of [6-5-6-6] steroid nucleus structure synthetic method (patent No.:
ZL201310184259.1 a kind of B- drop-D-homo- lactams sterides compound with [6-5-6-6] steroid nucleus structure) " is disclosed
The steroid nucleus structural formula of object, the compound is as follows:
Wherein:
X=O, NOH, NOCH3, NOCH2Ph, NNHCSNH2, NNHCSNHCH3, NNHCSNHCH2CH3, NNHCSNHPh.This
Invention has [6-5-6-6] steroid nucleus structure B- drop-D-homo- lactams steroidal compounds 5 to hepatoma cell strain, compound 10
It is inhibited with the growing multiplication of 11 pairs of colon cancer cell lines.Pharmaceutical intermediate or medicinal application be can be used as in different medicines
Object manufacture and purposes.As Chinese invention patent " 6- substitution -4- azepine-A-homo-3- oxo steroidal compounds and its in preparation it is anti-
Application (patent No.: ZL201010107528.0) in tumour medicine " discloses a kind of 6- substitution -4- azepine-A-homo-3- oxygen
For steroidal compounds, there is chemical structural formula shown in formula I:
Wherein X=OH ,=NOH, OSO3Na ,=O ,=NNH2 ,=NCSNH2 ,=NCONH2 ,=NCNHNH2 ,=
NNHCSNH2 ,=NNHCONH2, OCH2CH2N (R ') 2, N (CH2CH2Cl) 2, halogen ,=S, SH, OR ', wherein the R ' is general
Logical alkyl.R is to possess the straight chain of 1-14 C atom or replace the carbochain of branch with different location or possess different functional groups to take
The carbochain of Dai Ji, or containing different heteroatomic functional group such as OH ,=NOH, OSO3Na ,=O ,=NNH2 ,=NCSNH2,
=NCONH2 ,=NCNHNH2 ,=NNHCSNH2 ,=NNHCONH2, OCH2CH2N (R ') 2, N (CH2CH2Cl) 2, halogen ,=S,
SH,OR'.Experiments have shown that 6- substitution -4- azepine-A-homo-3- oxo steroidal compounds of the invention are to various tumor cell strains
It significantly inhibits, can be used for preparing the drug for the treatment of cancer.As China applies for patent of invention " 3- substitution-B-Homo-
Steroidal-B- cyclic lactam compound and preparation method thereof and application in preparation of anti-tumor drugs (application number:
201110009124.2, application publication number: CN102146115A) " disclose acyl in a kind of 3- substitution-B-Homo- steroidal-B- ring
Amine compounds and preparation method thereof and application in preparation of anti-tumor drugs.In the 3- substitution-B-Homo- steroidal-B- ring
Amide compound has such as the chemical structural formula in Formulas I:
Experiments have shown that 3- substitution-B-Homo- steroidal-B- cyclic lactam compound of the invention has various tumor cell strains
There is apparent inhibiting effect, can be used for preparing the drug for the treatment of cancer.
[summary of the invention]
The present invention provides a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone, preparation method
And application thereof, the anti-tumor drug that clinically uses is since it is more toxic caused by tissue to solve at present, greatly
The problem of limiting their use scope greatly.
In order to solve the above technical problems, the invention adopts the following technical scheme:
3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone structural formula of the invention is as follows:
The present invention introduces acetyl group on 3- using cholesterine as raw material, obtains 3- acetyl by being broken open loop after-condensation
Cholesteric compound drops in base-B-, then obtains 3- acetyl group -5- hydroxyl-B- norcholesterol-in 6- introducing N- methyl thiosemicarbazides
6- (N- methyl) contracting ammonia sulphur hydrazone.
From cholesterine, by following chemical equation synthesising target compound:
Scheme 1-1
Reagent and reaction condition: (a) CH2Cl2/triethylamin；(b)O3/(CH3)2S；(c)Al2O3/Ph；
(d)NH2NHCSNHCH3
Further, fracture open loop is carried out under conditions of being passed through ozone.
Further, condensation is the aldol reaction carried out at room temperature using neutral alumina.
It is anti-in preparation that the present invention also provides a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazones
Application in tumour medicine.
Further, neoplastic disease includes one of liver cancer, lung cancer, gastric cancer, cervical carcinoma, prostate cancer, colon cancer.
The invention has the following advantages:
3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone produced by the present invention to liver cancer, lung cancer,
The various tumor cell strains such as gastric cancer, cervical carcinoma, prostate cancer, colon cancer significantly inhibit, and toxicity is low, are not easy
Generate drug resistance；The present invention also provides the preparation method of the compound and purposes, and preparation method is simple for this, are conducive to city
Field promotes and applies.
[specific embodiment]
It to facilitate a better understanding of the present invention, is illustrated by following embodiment, these embodiments belong to of the invention
Protection scope, but do not limit the scope of the invention.
The present invention introduces acetyl group on 3- using cholesterine as raw material, obtains 3- acetyl by being broken open loop after-condensation
Cholesteric compound drops in base-B-, then obtains 3- acetyl group -5- hydroxyl-B- norcholesterol-in 6- introducing N- methyl thiosemicarbazides
6- (N- methyl) contracting ammonia sulphur hydrazone.
From cholesterine, by following chemical equation synthesising target compound (compound 2, compound 3, compound 4):
Scheme 1-1
Reagent and reaction condition: (a) CH2Cl2/triethylamin；(b)O3/(CH3)2S；(c)Al2O3/Ph；
(d)NH2NHCSNHCH3
It is more abundant in order to disclose the present invention, it is illustrated below by more specific embodiment.
Embodiment 1
The synthesis of compound 2
Cholesterol 386mg (1mmol) is weighed in the pyriform reaction flask of 100mL, the methylene chloride room temperature that 20mL is added is stirred
It mixes to cholesterol and dissolves, 1mL triethylamine is added, 1mL chloroacetic chloride is added, is stirred to react 4 hours under the conditions of 40 DEG C, TLC tracking is anti-
It answers, stops reaction after without obvious raw material.Thick column was carried out with ethyl acetate, vacuum distillation removes extra ethyl acetate and two
Chloromethanes is dissolved with methylene chloride, is washed respectively with saturated sodium bicarbonate solution, saturated sodium chloride solution, is successively extracted three times,
Merge organic phase, solvent is removed under reduced pressure, obtains solid crude product, column chromatography for separation obtains target product compound 2.White is solid
Body: m.p.109~112 DEG C1H NMR(CDCl3, 300MHz) and δ: 0.70 (3H, s, C18-H), 0.87 (3H, d, C26-H), 0.90
(3H, d, C27-H), 0.93 (3H, d, C19-H), 1.04 (3H, s, C21-H), 2.05 (3H, s, CH3), 4.64 (1H, m, C3-
H), 5.39 (1H, m, CH-6)13C NMR(CDCl3, 75MHz) and δ: 170.52 (C=O), 139.66 (5-C), 122.64 (6-C),
73.99,56.69,56.15,50.04,42.32,39.52,38.13,36.59,35.79,31.90,31.87,28.01,
23.83,22.82,22.56,21.43,19.31,18.72,11.86.IR(KBr)v/cm-1:3451.24,3144.64,
2955.19,2867.95,2820.59,2720.88,1723.79,1439.62,1464.55,1362.35,1245.19,
1140.50,1035.80,975.98,953.54,903.69,794.01,736.68,659.40,614.53.HREIMS calcd
for C29H48O2K[M+K]+467.3291,found 467.3274。
Embodiment 2
The synthesis of compound 3
The corresponding precursor compound 2 of 2mmol is weighed in eggplant shaped reaction bottle, the methylene chloride dissolution of 30mL, drop is added
The methanol for adding 5mL, is passed through O3, solution appearance blue, reaction 2 hours, TLC, which is tracked, to react, and stopping is passed through O after no raw material point3, add
The dimethyl sulphide for entering 5mL, is stirred to react after 4 hours to depressurize and is spin-dried for, and obtains white oil object, continuously adds the dissolution of 20mL benzene,
It weighs 10mg neutral alumina to be added in reaction flask, continues stirring 5 hours, TLC tracking is reacted, and stops reaction after no raw material point.
Thick column was carried out with ethyl acetate, decompression steams most solvent, and crude product column chromatography for separation obtains target product compound
3, yield 60%.m.p.84~88 DEG C1H NMR(CDCl3,300MHz) δ: 0.74 (3H, s, C18-H), 0.86 (3H, d, C26-
H), 0.88 (3H, d, C27-H), 0.93 (3H, d, C19-H), 0.96 (3H, s, C21-H), 2.08 (3H, s ,-CH3), 5.15
(1H,m,OH),9.69(1H,s,CHO).13C NMR(CDCl3, 75MHz) and δ: 203.91 (CHO), 169.74 (C=O), 83.65,
70.36,64.53,56.00,55.65,51.51,45.59,44.64,42.20,39.46,39.34,36.17,35.60,
27.99,24.98,24.46,23.81,22.79,22.54,21.55,21.38,18.74,18.20,12.48.IR(KBr)v/
cm-1:3590.83,3172.06,2947.71,2867.95,1738.75,1693.88,1472.03,1387.27,1300.03,
1252.67,1185.36,1150.47,1053.25,975.98,906.18,866.30,818.94,724.21,622.01,
492.39.HREIMS calcd for C29H48O4Na[M+Na]+483.3450 found 483.3446.
Embodiment 3
The synthesis of compound 4
The corresponding precursor compound 3 of 1mmol is weighed in 100mL pyriform reaction flask, 20mL dehydrated alcohol, room temperature is added
Lower stirring and dissolving is added 4- methyl thio semicarbazides 110mg, reacts 5 hours under the conditions of 60 DEG C of temperature, TLC tracking reaction, nothing
Stop reaction after raw material point, decompression steams dehydrated alcohol.Crude product column chromatography for separation obtains (the 3- acetyl of target product compound 4
Base -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone).White solid, yield 60%.m.p.93~94 DEG C1H
NMR(CDCl3,300MHz)δ:0.68(3H,s,C18-H),0.86(3H,d,C26-H),0.88(3H,d,C27-H),0.92(3H,
d,C19-H),0.95(3H,s,C21-H),2.07(3H,s,CH3),4.62(1H,m,C3-H),5.39(1H,d,CH-6),7.08
(1H, m, NH-CH3), 7.40 (1H, m, CH=N), 9.09 (1H, S, NH)13C NMR(CDCl3, 75MHz) and δ: 187.37 (C=
), S 170.23 (3-C=O), 148.32 (6-C=N), 83.00 (5-C), 70.00 (3-C), 56.36 (17-C), 55.84 (14-
C),53.13(7-C),45.08(9-C),44.55(13-C),42.73(8-C),40.47(10-C),39.58(12-C),39.45
(24-C),36.19(4-C),35.58(22-C),30.50(NH--CH3),28.54(20-C),28.00(16-C),(24.89
(25-C),23.83(23-C),22.79(26-C),22.54(27-C),21.73(3ɑ-C),21.46(11-C),18.75(21-
C),18.26(19-C),12.38(18-C).IR(KBr)v/cm-1:3144.64,2950.21,2867.95,1723.79,
1544.31,1464.55,1397.24,1250.17,1073.19,1023.34,958.53,903.69,734.18；
HREIMScalcd.for C31H52N3O3S[M-H]-546.3729 found 546.3734.
Embodiment 4
The assessment of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone (compound 4) anti-tumor activity
In order to assess the external suppression of synthesized 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone
Growth of tumour cell proliferation activity processed, we are with MCF-7 (human breast cancer cell), SKOV3 (ovarian cancer cell), T47D (human milk
Gland ductal carcinoma cells), people's renal epithelial cell (HEK-293T) be used as research object, using mtt assay, to 3- acetyl group -5- hydroxyl -
B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone (compound 4) carries out the test of anti tumor activity in vitro, test data such as table 1
It is shown.
External inhibitory activity (the mtt assay) (IC of 1 compound of table 450,μmol/L)
By the test data of table 1 it is found that 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia of the invention
Sulphur hydrazone there is significant inhibition growth of tumour cell to increase human breast cancer cell, human milk gland ductal carcinoma cells, Proliferation of Human Ovarian Cell
Grow effect.
3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone toxicity of the invention is low, is not likely to produce
Drug resistance；In addition, the compounds process for production thereof is simple and easy, be conducive to marketing application.
The specific implementation of the invention is not to be limited to these illustrations for the above content, and technology belonging to the present invention is led
For the those of ordinary skill in domain, without departing from the inventive concept of the premise, a number of simple deductions or replacements can also be made,
It all shall be regarded as belonging to present invention scope of patent protection determined by the appended claims.
Claims (6)
1. a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone, which is characterized in that it is with following
Chemical structural formula:
2. a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone according to claim 1
Preparation method, which comprises the following steps: using cholesterine as raw material, acetyl group is introduced on 3-, by breaking apart
Ring after-condensation obtains 3- acetyl group-B- drop cholesteric compound, then obtains 3- acetyl group-in 6- introducing N- methyl thiosemicarbazides
5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone.
3. the preparation of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone according to claim 2
Method, which is characterized in that fracture open loop is carried out under conditions of being passed through ozone.
4. the preparation of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone according to claim 2
Method, which is characterized in that condensation is the aldol reaction carried out at room temperature using neutral alumina.
5. a kind of 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone according to claim 1 exists
Prepare the application in anti-tumor drug.
6. prepared by 3- acetyl group -5- hydroxyl-B- norcholesterol -6- (N- methyl) contracting ammonia sulphur hydrazone according to claim 1
Application in anti-tumor drug, which is characterized in that neoplastic disease includes liver cancer, lung cancer, gastric cancer, cervical carcinoma, prostate cancer, colon cancer
One of.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286066A (en) * | 2011-08-24 | 2011-12-21 | 广西师范学院 | Preparation method and application of 6-oxo-7-oxa-B-Homo-cholest-3-semicarbazone sulfurylhydrazone compound to preparation of antitumor drug |
| CN103214542A (en) * | 2013-04-18 | 2013-07-24 | 广西师范学院 | B-nor-6-(4'-alkyl) aminothizone cholestane compound, and preparation method and application thereof in anticancer drugs |
| CN104447937A (en) * | 2014-12-17 | 2015-03-25 | 广西师范学院 | B-norcholestane benzimidazole compound as well as preparation method and application thereof |
| CN109824748A (en) * | 2019-03-26 | 2019-05-31 | 广西万德药业有限公司 | B- norcholesterol oxidized derivatives and its synthetic method and application |
-
2019
- 2019-07-31 CN CN201910704702.0A patent/CN110330543A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102286066A (en) * | 2011-08-24 | 2011-12-21 | 广西师范学院 | Preparation method and application of 6-oxo-7-oxa-B-Homo-cholest-3-semicarbazone sulfurylhydrazone compound to preparation of antitumor drug |
| CN103214542A (en) * | 2013-04-18 | 2013-07-24 | 广西师范学院 | B-nor-6-(4'-alkyl) aminothizone cholestane compound, and preparation method and application thereof in anticancer drugs |
| CN104447937A (en) * | 2014-12-17 | 2015-03-25 | 广西师范学院 | B-norcholestane benzimidazole compound as well as preparation method and application thereof |
| CN109824748A (en) * | 2019-03-26 | 2019-05-31 | 广西万德药业有限公司 | B- norcholesterol oxidized derivatives and its synthetic method and application |
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